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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1477-1483
IMMUNOBIOLOGY
Distinct contributions of TNF and LT cytokines to the development
of dendritic cells in vitro and their recruitment in
vivo
Koichiro Abe,
Felix O. Yarovinsky,
Takaya Murakami,
Alexander N. Shakhov,
Alexei V. Tumanov,
Daisuke Ito,
Ludmila N. Drutskaya,
Klaus Pfeffer,
Dmitry V. Kuprash,
Kristin L. Komschlies, and
Sergei A. Nedospasov
From the Laboratory of Molecular Immunoregulation and
Laboratory of Experimental Immunology, Center for Cancer Research and
Basic Research Program, SAIC Frederick, National Cancer Institute,
Frederick, MD; Engelhardt Institute of Molecular Biology, Russian
Academy of Sciences, and Belozersky Institute of Physico-Chemical
Biology, Moscow State University, Moscow, Russia; and
Institute for Medical Microbiology, Immunology and Hygiene, Technical
University of Munich, Germany.
TNF/LT /LT (tumor necrosis
factor/lymphotoxin-/lymphotoxin-) triple knockout (KO) mice show
a significant reduction of dendritic cell (DC) number in the
spleen, presumably due to defective recruitment and/or production. To
distinguish between these possibilities, DCs were generated from bone
marrow (BM) cultures prepared from wild-type (wt) and mutant mice in
the presence of granulocyte-macrophage colony-stimulating factor
(GM-CSF) and interleukin-4 (IL-4). The yield of CD11c+
major histocompatibility complex (MHC) class II+
DCs generated from TNF/LT/LT / BM culture was
significantly reduced compared with wt BM culture. In order to further
dissect the individual pathways responsible for defective DC properties
observed in TNF/LT/LT/ mice, the panel of TNF/LT
ligand and receptor single KO mice were used. The production of DCs
from BM culture was significantly reduced in TNF/ and
TNF receptor (TNFR) p55/ mice, but normal in
LT/, LT/, LTR/
mice. Recombinant TNF (rTNF) exogenously added to
TNF/LT/LT/ BM cultures could reverse this defect,
and blocking antibodies showed partial effect on BM cultures of wt
mice. Conversely, numbers of mature DCs in spleen were significantly
decreased in LT/, LT/,
LTR/ mice, but not in TNF/ and
TNFRp55/ mice. These results reveal 2 distinct
contributions of TNF/LT cytokines. First, TNF acting through TNF
receptor is involved in the development/maturation of DCs in BM
progenitor cultures, but this function appears to be redundant in vivo.
Second, the microenvironment in peripheral lymphoid organs associated
with LT/LT-LTR signaling and chemokine production is critical
for recruitment efficiency of DCs, and this pathway is indispensable.
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